a phase 1 study to evaluate the safety and tolerability of tt-01488 in patients with b-cell malignancies

Conditions: B-Cell Malignancies

Summary: this is a multicenter, open-label phase i dose escalation study to evaluate the safety and preliminary efficacy of the tt-01488 tablet, a non-covalent reversible btk inhibitor, for the treatment of adult patients with b-cell malignancies.

the study will consist of two parts, dose escalation and dose expansion. a modified 3+3 design will be used to guide the dose escalation and the determination of the dose recommended for dose expansion (drde). a sentinel cohort comprising of one subject will be enrolled at a starting dose of 50 mg q.d. subsequently, patients will be enrolled according to the standard 3+3 dose escalation design to determine the drde. once the drde has been selected, tt-01488 of drde will be further tested in the dose expansion cohort to verify the safety and preliminary efficacy as observed in the dose escalation cohorts. a recommended phase ii dose (rp2d) may be determined based on the totality of safety, pharmacokinetics, and efficacy data from the dose escalation cohorts and dose expansion cohort.

Eligibility criteria:
inclusion criteria: * participants with histologically confirmed b-cell malignancy, failed or intolerant to either ≥ 2 prior standard/common regimens given in combination or sequentially or have received 1 prior btk-containing regimen, relapse/refractory, and with treatment indication: * cll/sll treated with prior immunochemistry or btk inhibitor containing regimen; * dlbcl treated with prior cd20 or anthracyclines containing regimen; * other types of b-cell nhl treated with prior cd20 containing regimen * adequate organ function, defined by the following laboratory parameters: * hematologic: * absolute neutrophil count (anc) ≥ 0.75×10\^9/l, and ≥ 0.5×10\^9/l if bone marrow involved * platelets ≥ 50×10\^9/l without transfusion within 7 days, and ≥ 30×10\^9/l if bone marrow involved * hemoglobin ≥ 8.0 g/dl without transfusion within 7 days, and ≥ 7.0 g/dl if bone marrow involved * coagulation: * prothrombin time (pt) ≤ 1.5 × uln * activated partial thromboplastin time (aptt) ≤ 1.5 × uln * renal function: * creatinine clearance ≥ 30 ml/min estimated glomerular filtration rate based on cockcroft-gault formula * liver function: * total bilirubin ≤ 1.5 × uln (unless due to gilbert's disease) * aspartate aminotransferase (ast) or alanine aminotransferase (alt) ≤ 2.5 × uln unless disease-related exclusion criteria: * women who are pregnant or lactating * prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease-free for at least 2 years or which will not limit survival to \< 2 years (note: these cases must be discussed with the medical monitor and/or investigator) * significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or significant screening ecg abnormalities * malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction * history of allogeneic or autologous stem cell transplant (sct) or chimeric antigen receptor-modified t-cell (car-t) therapy within the past 60 days or with any of the following: * active graft versus host disease (gvhd); * cytopenias from incomplete blood cell count recovery post-transplant; * need for anti-cytokine therapy for toxicity from car-t therapy; residual symptoms of neurotoxicity \> grade 1 from car-t therapy; * ongoing immunosuppressive therapy * grade ≥ 2 toxicity (other than alopecia) continuing from prior anticancer therapy, including radiation